Project Summary Infection with the human immunodeficiency virus (HIV) causes severe immunodeficiency that can be associated with increased frequency of other infections and with the reactivation of latent pathogens. The majority of HIV infections occur in sub-Saharan Africa, a region that is also a fulminant epicenter of the global malaria pandemic. The number of malaria cases and deaths is staggering: 300-500 million cases and 1-2 million deaths are reported every year. More than 90% of the fatalities occur in sub-Saharan Africa and these result from infection with Plasmodium falciparum, the most important human malaria parasite. Despite the recognition that HIV-P. falciparum co-infection is a major health threat, the impact of this co-infection on morbidity and mortality is not well known. In addition, the paucity of data on mechanisms contributing to enhanced HIV replication in malaria-coinfected individuals and on the clinical and epidemiological implications for transient viral load increases and enhanced parasitemia in co-infected individuals indicate a critical need for definitive studies of co-infection synergy. Thus, we propose to establish a rhesus macaque co-infection model of SIV and the simian parasite Plasmodium fragile to closely mimic HIV-P. falciparum co-infection in humans. We hypothesize that enhanced pathology of SIV and malaria in co-infected versus singly infected macaques will result from altered immunologic response mechanisms. Aim 1 of the proposed studies will examine the effect of malaria infection on SIV pathogenesis by measuring viral load, immune activation and SIV-specific immune responses. In Aim 2 the effect of SIV on P. fragile infection will be determined by examining the kinetics and levels of parasitemia and gametocytemia, transmission to mosquitos, and the frequency of recurrent malaria episodes. We predict that this model will provide critical insights into the immunological correlates that exacerbate both infections and that potentially lead to enhanced transmission. Further, this model will be informative for vaccine and therapeutic strategies that must accommodate the potential for enhanced and reduced efficacies in co-infected patients. Narrative Sub-Saharan Africa is an epicenter for both HIV/AIDS and malaria. While the global health problem of each of the diseases is well recognized, the impact of co-infection on morbidity and mortality is not known. The goal of this application is to develop a rhesus macaque model of SIV-malaria infection to study immune responses, virological outcome and parasite load in co-infected animals versus singly infected animals to define mechanisms that cause disease exacerbation and increased transmission rates in co-infected individuals.